tbuckley/cabot-search huggingface dataset:
TMIC-30. HYPOXIA-INDUCED COMPLEMENT COMPONENT 3 PROMOTES AGGRESSIVE TUMOR GROWTH IN THE GLIOBLASTOMA MICROENVIRONMENT
Authors: Rebecca Rosberg, Karolina Smolag, Jonas Sjölund, Elinn Johansson, Christina Bergelin, Julia Wahldén, Vasiliki Pantazopoulou, Kristian Pietras, Crister Ceberg, Anna Blom, Alexander Pietras
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is the most aggressive primary adult brain tumor. Treatment includes surgery, irradiation and chemotherapy. Still, virtually all patients suffer a treatment resistant recurrent tumor. In previous studies from our lab, we have investigated the tumor microenvironment contribution to tumor progression, showing that stromal astrocytes become reactive upon irradiation and hypoxia and generate tumor-supportive conditions for glioblastoma cells. Common features of astrocyte reactivity in several neurological diseases, include upregulation of complement proteins including complement component 3 (C3). However, it remains unexplored if these complement proteins are expressed in stromal astrocytes in glioblastoma. In a genetically engineered glioma mouse model, C3 was expressed in the invasive front, hypoxic, and perivascular tumor areas. TCGA data analysis revealed an overall strong correlation between hypoxia and complement gene expression signatures in glioblastoma patients. Astrocytes and glioma cells cultured in hypoxic conditions upregulated C3, as well as other genes associated with an infiltrative phenotype of GBM. In hypoxia, glioma cell lines, but not astrocytes, upregulated the C3a Receptor. GBM tumor single-cell sequencing data confirmed a subpopulation of highly C3-expressing astrocytes, enriched for cellular pathways comprising epithelial mesenchymal transition (EMT), TNF-alpha, hypoxia, and IFN-signaling. In vitro, C3 enhanced proliferation of glioma cells specifically under hypoxic conditions. Blocking C3a-C3aR signaling in vivo prolonged survival of glioma-bearing mice both alone and in combination with radiotherapy. Overall, our data indicate a strong link between hypoxia and complement expression in the brain tumor microenvironment of glioblastoma, where local expression of complement proteins lead to tumor promoting signaling. Inhibition of C3a-C3aR enhanced survival of glioma-bearing mice and could represent a promising avenue for further investigations.
SURG-30. CLINICAL CONSIDERATIONS, APPROACH SELECTION, AND OUTCOMES ASSOCIATED WITH TREATMENT STRATEGIES FOR FALCOTENTORIAL MENINGIOMAS: SYSTEMATIC REVIEW AND META-ANALYSIS OF THE CURRENT EVIDENCE
Authors: Nolan Brown, Basel Musmar, Cathleen Kuo, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Meningiomas at the falcotentorial (FT) junction are rare, as they account for only 0.3%-1.1% of all intracranial meningiomas. Clinical management of FT meningiomas can be challenging. METHODS The authors queried three databases per PRISMA guidelines to identify all studies reporting indications for surgical resection of FT meningioma. RESULTS Thirty studies reporting 224 FT patients met pre-specified inclusion criteria. Patients diagnosed with FT meningioma demonstrated a predilection for headache on initial examination (p = 0.030).Headache was the mostly commonly reported symptom, present more often than visual disturbance (RR 2.28 [1.59, 3.26], I2=0%, P &amp;lt; 0.00001), ataxia or imbalance (RR 0.21 [0.08, 0.35], I2= 0%, P = 0.002), and cognitive disturbance (RR 0.34 [0.20, 0.47], I2 = 12%, P &amp;lt; 0.00001). An overwhelming majority of lesions (n = 97, 80.2%) were benign, WHO Grade I. The primary arterial feeders supplying the FT lesions were reported in 13 studies; most commonly, these arterial feeders included the distal branches of the ICA (n = 29), ECA (n = 25), and vertebrobasilar vasculature (n = 35). Visual deficits (n = 32, 14.3%) were the most common postoperative complication.Bassiouni classification of the tumors was reported in 10 studies, with 27 (31.8%) classified as type I, 16 (18.8%) as type II, 37 (43.5%) as type III, and five (5.9%) as type IV FT meningiomas.Simpson Grade I resection (n = 76, 43.7%) was achieved in slightly less than half of cases. Cases involving multi-stage resections appeared to confer greater risk (RR 1.42 [0.72, 2.80], I2=0%, P = 0.31) for STR (failure to achieve GTR or Simpson Grade I resection). CONCLUSION The primary objective when treating FT meningiomas is to achieve gross total resection (GTR) or Simpson Grade 1 resection. Grade 2 resection is also regarded as a good outcome for these lesions. This goal should be pursued while minimizing cerebellar retraction and protecting vital vascular structures, such as the Galenic venous system.
PATH-57. WHOLE EXOME SEQUENCING OF INTRACRANIAL EPIDERMOID CYSTS (IECS) REVEALS POTENTIAL SOMATIC DRIVERS
Authors: Shruthi Kondaboina, Carolina Da Silva Parada, Manuel Ferreira
Journal: Neuro-Oncology (2023)

Abstract Intracranial Epidermoid Cysts (IECs) are benign, slow-growing, asymptomatic tumors with an incidence rate of 1% of all intracranial tumors. They are significantly enlarged when discovered and can cause seizures. IECs are suspected to form due to disruptions in neural tube closure. Given their rarity, formation of IECs is under-investigated and surgery is the only treatment option. However, because the cyst lining can be adherent to important brain structures, resection is challenging and can result in post-operative complications, highlighting the need to investigate the pathogenesis of IECs to develop drug therapeutic options. We performed paired-end Whole Exome Sequencing (WES) on DNA from six sporadic IECs. Data processing of raw unmapped reads was performed in tumor-normal and tumor-only mode as appropriate, following GATK best practices for variant calling. We identified 2,850 SNPs and 2,102 indels in this cohort. We identified two common variants, NKX2.5 (p.P214del) and STIM-1 (p.T576del, p.T502del) across all samples, which is a novel finding. We also identified 27 genes and variants shared variably across the samples. Gene enrichment analysis revealed that the Sonic Hedgehog (SHH) pathway is implicated in these gene sets due to activating mutations in the SMO gene (p.L23del). We are using an immunohistochemical stain to validate this finding. The mutant NKX2.5, a transcription factor (TF) responsible for stem-cell differentiation in embryogenesis, strongly indicates that the tumor microenvironment (TME) is disrupted. Deletions in the STIM-1 gene indicate loss of interaction with Orai1 calcium channels, disrupting store operated Ca2+ entry (SOCE) and preventing typical cell migration, resulting in trapped fibroblasts. Digital droplet PCR (ddPCR) of these samples is underway to validate the low tumor allele frequencies (&amp;lt; 4%). The discovery of activating mutations in SMO is significant because it potentiates FDA-approved SMO-inhibitors like Vismodegib and Sonidegib as viable treatment options for patients with IECs.
NIMG-46. MULTI-PARAMETRIC MRI RADIOMIC ANALYSIS USING DEEP LEARNING PREDICTS PERITUMORAL GLIOBLASTOMA INFILTRATION AND SUBSEQUENT RECURRENCE
Authors: Sunwoo Kwak, Hamed Akbari, Jose Garcia, Suyash Mohan, Christos Davatzikos
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Glioblastoma (GBM) is the most aggressive and infiltrative brain tumor with a very poor prognosis which hasn’t significantly improved in over 20 years. The almost 100% recurrence rate is due to cancer infiltration beyond the tumor margins currently being targeted by standard of care. Prior studies used traditional supervised machine learning have shown great promise in predicting tumor infiltration beyond these margins. We hypothesize that deep learning methods can further improve such predictive maps and guide intensive, yet targeted and personalized therapies. METHODS MRIs from a cohort of 109 de novo GBM patients were collected from Hospital of the University of Pennsylvania. All the patients incorporated in this study had pre-operative multi-parametric MRI scans including T1, T1Gd, T2, T2-FLAIR, ADC, and underwent surgical resection followed by standard chemoradiation therapy and had pathologically confirmed recurrence. A novel, automated deep learning method, informed by results of prior studies using support vector machines, was constructed to train a patch-based ensemble CNN to identify regions of peri-tumoral cancer infiltration. Leave-one-out was used to evaluate the predictive value of this method, against pathology-proven subsequent recurrence. RESULTS Probability maps, representing the likelihood of tumor infiltration and eventual recurrence, were binarized using threshold of 50% cutoff, compared with actual recurrence on post-recurrence MRI scans. The average cross-validated accuracy was 92%, specificity was 93%, patient-based sensitivity was 78%, and odds-ratio among all patients was 12.95 (Estimated “hot spots” were 12.95 times more likely to present recurrence in the future). CONCLUSIONS This study demonstrates that Multi-parametric MRI pattern analysis using CNN based network can successfully predict tumor infiltration in peritumoral region for Glioblastoma patients. These suggest that new intensive, yet precisely targeted treatments can be developed, guided by AI-driven predictive maps of infiltration.
TMET-12. <i>CDKN2A</i> DELETION REMODELS LIPID METABOLISM TO PRIME GLIOBLASTOMA FOR FERROPTOSIS
Authors: Jenna Minami, Danielle Morrow, Nicholas Bayley, Elizabeth Fernandez, Jennifer Salinas, Christopher Tse, Henan Zhu, Baolong Su, Alessandro Sammarco, Linda Liau, Thomas Graeber, Kevin Williams, Timothy Cloughesy, Scott Dixon, Steven Bensinger, David Nathanson
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas (GBM) are universally lethal brain tumors that exhibit extensive genetic and transcriptional heterogeneity. GBMs acquire metabolic adaptations in response to a multitude of intrinsic (oncogenotype) and extrinsic (tumor microenvironment) factors to fuel neoplastic progression. Large-scale multi-omic studies in cancer cell lines have further advanced our understanding of the intersection between molecular diversity and metabolic heterogeneity, indicating distinct metabolic vulnerabilities may exist within defined molecular subsets of cancer. However, the translatability of these observations into effective cancer therapies remains limited due to gaps in our understanding of the physiologic fidelity of metabolic studies conducted only in vitro. Thus, accounting for both the molecular diversity and environment of human tumors is crucial to identify translatable metabolic targets.
CTIM-26. IMPACT ON SURVIVAL OF INTERFERON-ALPHA DELIVERY IN GLIOBLASTOMA WITH UNMETHYLATED MGMT BY IMMUNO-GENE THERAPY WITH TEMFERON
Authors: Gaetano Finocchiaro, Valeria Cuccarini, Bernhard Gentner, Alessia Capotondo, Francesca Farina, Matteo Maria Naldini, Matteo Barcella, Elena Anghileri, Maria Grazia Bruzzone, Matteo Carrabba, Quintino Giorgio D'alessandris, Francesco Di Meco, Valeria Ferla, Alberto Franzin, Paolo Ferroli, Filippo Gagliardi, Federico Legnani, Stefania Mazzoleni, Pietro Mortini, Alessandro Olivi, Roberto Pallini, Monica Patanè, Rosina Paterra, Bianca Pollo, Marco Saini, Silvia Snider, Karen Mullen, Luigi Naldini, Carlo Russo, Fabio Ciceri, Marica Eoli
Journal: Neuro-Oncology (2023)

Abstract Temferon is an ex vivo gene therapy consisting of autologous Hematopoietic Stem Progenitor Cells (HSPCs) genetically modified with a lentiviral vector to deliver IFN-α2 within the tumor microenvironment by Tie-2 expressing macrophages. TEM-GBM is an open-label, Phase I / IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 27 newly diagnosed GBM patients with unmethylated MGMT (uMGMT). As of 30th April 2023, 19 GBM patients in 4 cohorts received incremental doses of Temferon and four are still alive after a median follow-up of 15 months. Six of the treated patients underwent a second surgical intervention at a median of 11 months after 1st surgery. For all patients, median overall survival (OS) and median progression free survival following first surgery reach 15 months and 9.8 months from diagnosis, respectively. The interim survival rate at 2 years in Temferon-treated patients is 28% (5 of 18 patients; 1 patient excluded as follow-up is below 1 year). OS and survival rate at 2 years of uMGMT patients treated as per the current standard of care (SOC) is 12.7 months and 14,8% respectively. One out of the surviving patients is alive 3 years after first surgery without second line therapy added up to 2 years. The other four patients with 2 year follow-up were treated with Gamma-Knife followed by bevacizumab (n = 1), regorafenib followed by bevacizumab (n = 1) and bevacizumab only (n = 2). Bevacizumab administration started 12 months after 1st surgery for one patient and 19 months for the other 2 patients at 5 mg/kg. These data corroborate the initial evidence on safety and tolerability of Temferon. They also suggest that Temferon has potential to counteract disease progression in patients affected by uMGMT GBM.
NIMG-64. IN VIVO METABOLIC PROFILING FOR RECURRENT GLIOMA
Authors: Yan Li, Marisa Lafontaine, Adam Autry, Fei Jiang, Anny Shai, Joanna Phillips, Susan Chang
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The 2021 WHO classification has identified the importance of molecular features in diagnosing adult glioma. The goal of this study was to use short echo MR spectroscopic imaging (MRSI) to evaluate the metabolite profiles at recurrence and characterize in vivo metabolism in relation to pathology by combining it with image-guided tissue samples. METHODS Fifty-one patients with an initial diagnosis of glioma (18 astrocytoma, 14 oligodendroglioma, and 19 glioblastoma) received MR examinations before surgical resection of progressive disease confirmed histologically. The 3D MRSI data were combined, processed, and quantified by LCModel with a simulated basis set. Metabolite levels were compared between contrast-enhancing lesions (CEL), non-enhancing lesions (NEL), and patient groups. Spectra data centered at the tissue target location were correlated to pathological parameters from the samples (0-4 samples/subject). RESULTS 74.5% (38/51) patients had enhancing tumors, with median CEL volume of 4.2 cm3 (min-max: 0.2-28.5 cm3) and median NEL volumes of 50.6 cm3 (4.8-167.2 cm3). The patients with GBM had significantly larger CEL volumes than the others (p=0.009).18/29 (62%) patients with lower-grade glioma had malignant progression to higher grades. Those who progressed from grade 2 to 3 or 4 had higher myo-inositol/choline (mean±SD, 2.62±0.64, N=18) compared to those who recurred as grade 2 (1.88±0.52, N=5, p = 0.015). Of the 51 patients, 40/65 in vivo spectra voxels centered where the tissues were sampled displayed good quality, with 27 having active tumors, 7 having treatment effects, and 6 having mixed tumors/treatment effects. The levels of choline/creatine and myo-inositol+glycline/creatine were significantly correlated with MIB-1 (p&amp;lt; 0.0001, =0.034; r=0.563, 0.349), but no difference was found between the locations with active tumors and treatment effects. DISCUSSION: This study demonstrated metabolite variations at the recurrence. Ongoing studies will further characterize the metabolite profiles for malignant progression and differences between active tumors and treatment effects.
NIMG-62. QUANTITATIVE ASSESSMENT OF T2-FLAIR MISMATCH IN HUMAN NON-ENHANCING GLIOMAS USING SUBTRACTION MAPS OF T2-W AND FLAIR MRI
Authors: Nicholas Cho, Francesco Sanvito, Vien Le, Sonoko Oshima, Ashley Teraishi, Jingwen Yao, Catalina Raymond, Whitney Pope, Phioanh Nghiemphu, Albert Lai, Timothy Cloughesy, Noriko Salamon, Benjamin Ellingson
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The T2-FLAIR mismatch (T2FM) sign on anatomical MRI is highly specific for isocitrate dehydrogenase (IDH)-mutant 1p/19q-intact gliomas (astrocytomas) and is characterized by relative hypointense FLAIR signal within the T2 hyperintense lesion. However, studies on T2FM sign have mostly utilized qualitative visual assessment. This study explored quantitative subtraction maps of T2-w and FLAIR MRI in human non-enhancing gliomas to quantify the extent of T2FM and assess T2FM subregion volumetric and diffusion MRI differences. METHODS Seventy-two newly-diagnosed, non-enhancing gliomas with known IDH- and 1p/19q-status from The Cancer Imaging Archive (TCIA) were studied. An institutional cohort (n= 36) was analyzed for validation. T2-FLAIR subtraction maps were generated from voxel-wise subtraction of co-registered, normalized T2-w and FLAIR MRI scans. Tumor volumes of interest (VOIs) were segmented on the T2 hyperintensity excluding macroscopic cysts. Tumor VOIs were split into mismatched and non-mismatched subregions using consistent T2-FLAIR subtraction map thresholds. Tumor subregion volumes and normalized apparent diffusion coefficient (nADC) values were obtained, and tumor T2FM percentage was calculated. RESULTS In the TCIA cohort, a threshold of &amp;gt; 16% T2FM had 92.3% specificity and 34.8% sensitivity and a threshold of &amp;gt; 42% T2FM had 100% specificity and 21.7% sensitivity for classifying IDH-mutant astrocytomas (AUC= 0.704, P= 0.004). IDH-mutant astrocytomas with &amp;gt; 16% T2FM had higher nADC in mismatched compared to non-mismatched subregions (mean difference= 0.51; P&amp;lt; 0.0001). Using the same T2FM thresholds, these findings were validated in the institutional cohort for glioma classification (AUC= 0.918, P&amp;lt; 0.0001; &amp;gt; 16% T2FM: 100% specificity, 66.7% sensitivity, PPV= 100%, NPV= 65.2%; &amp;gt; 42% T2FM: 100% specificity, 23.8% sensitivity, PPV= 100%, NPV= 48.3%) and subregion nADC differences (mean difference= 0.56, P&amp;lt; 0.0001). CONCLUSIONS T2-FLAIR subtraction maps may be a useful, automated tool for classifying non-enhancing gliomas and exploring T2FM subregion differences. Elevated nADC in mismatched subregions may reflect microcystic changes.
EXTH-42. PRECLINICAL INVESTIGATION OF A NOVEL BRAIN PENETRANT MEK INHIBITOR TO TARGET BRAIN METASTASIS
Authors: Erika Yamazawa, Naema Nayyar, Nazanin Ijad, Consuelo Torrini, Magali De Sauvage, Christian Migliarese, Elizabeth Summers, Braxton Marion, Catherine Lee, Rowena Suriben, Michelle Perez, Ben Powell, Nichol Miller, Brooke Grandinetti, Hiroaki Wakimoto, Priscilla Brastianos
Journal: Neuro-Oncology (2023)

Abstract Melanoma is one of the most common cancers with a high rate of brain metastases, with up to 75% of cases showing brain metastases upon autopsy. BRAF mutations are common in melanoma and found in up to 50-55% of melanoma brain metastases. Despite the clinical success of BRAF/MEK inhibitors for the treatment of advanced melanoma, dabrafenib and vemurafenib have limited intracranial overall response rates of 42-50% and median progression-free survival of 3.6-5.5 months. This limited efficacy is in part attributed to minimal blood-brain barrier penetration of the current available inhibitors. The goal of this study was to characterize a novel MEK inhibitor KIN-7136 as a potential therapeutic agent for brain metastasis driven by aberrant BRAF-MEK signaling, such as BRAF-mutant melanoma, using in vitro assays and an in vivo model of metastasis. KIN-7136 showed improved rodent brain exposure compared to conventional agents; the brain-to-plasma concentration ratio (Kp) of KIN-7136 was &amp;gt;1.0, much higher than comparators binimetinib and mirdametinib. In vitro cell viability assays showed potent cytotoxic effects of KIN-7136, with IC50s ranging from 15.4 to 204.9 nM in models of MAPK dysregulation including A375 (melanoma, BRAFV600E), NCI-H2405 (lung adenocarcinoma, BRAFΔNVTAP), HMVII (melanoma, BRAFG469V), and LN001 (patient derived lung adenocarcinoma, KRASG12V). Western blotting for phospho-ERK confirmed KIN-7136-mediated on-target downstream suppression in the A375 cell line. In vivo, daily oral treatment with KIN-7136 was well tolerated and produced a significant extension of overall survival compared to the vehicle control (p=0.0289, log-rank test) in the A375 intracranial tumor model in athymic mice. These preclinical data confirm activity of KIN-7136 in BRAF-mutant melanoma brain metastases models and support further research to advance its clinical progression.
TMET-16. ELUCIDATING MECHANISMS OF ENHANCED OXIDATIVE PHOSPHORYLATION IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Fares Burwag, Alberto Delaidelli, Betty Yao, Gian Luca Negri, Yue Zhou Huang, Albert Huang, Andrii Vislovukh, Sonya Langman, Christopher Hughes, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MBL) is the most commonly diagnosed pediatric brain tumour and the leading cause of childhood cancer deaths. MYC overexpression often accompanies poor prognosis in MBL patients, as MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). However, it also induces a high metabolic demand that impairs cell survival under acute nutrient deprivation. We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, is overexpressed in MYC-driven MBL. Preliminary data suggests a relationship between eEF2K-mediated selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MBL. Multiplexed enhanced Protein Dynamic Mass Spectrometry was carried out in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. 9 of 10 detected components of the OXPHOS pathway were selectively translated in eEF2K-active MBL cells. Genetic eEF2K knockout led to the disassembly of electron transport chain (ETC) complexes I-V and reduced complex activity, as observed via Blue Native PAGE and colorimetric assays. Furthermore, siRNA knockdown of Cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial OXPHOS assembly factor differentially expressed in eEF2K active or inactive D425 cells, produces the same pattern of supercomplex (SC) loss as the inactivation of eEF2K in wild-type D425 cells. The assembly of ETC SC across D425 eEF2K active and inactive cells was further studied using blue native gel-based mass spectrometry to further characterize patterns in SC loss. In summary, control of translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MBL, likely representing an adaptive response against acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetics.